Neuroprotective effects of AEOL 10150 against organophosphate toxicity

AEOL 10150 对有机磷毒性的神经保护作用

• 批准号: 8921304
• 负责人: MANISHA N PATEL
• 金额: $ 92.83万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921304
• 关键词: 3-nitrotyrosine; 4 hydroxynonenal; Adverse event; Animals; Antioxidants; Biochemical; Biological Availability; Blood - brain barrier anatomy; Cessation of life; Chemical Exposure; Chemical Warfare Agents; Chemicals; Chlorine; Clinical Trials; Data; Deoxyguanosine; Development; Dose; Drug Kinetics; Electroencephalography; Excision; Experimental Models; Frequencies; Gliosis; Glutathione Disulfide; Goals; Health; Human; Hydrogen Peroxide; Impaired cognition; Incidence; Individual; Injectable; Insecticides; Iran; Iraq; Laboratories; Lead; Lipids; Literature; Measures; Medical; Military Personnel; Modeling; Monitor; Mustard; Mustard Gas; Neuraxis; Neuronal Injury; Neurons; Organophosphates; Oxidative Stress; Permeability; Peroxonitrite; Pesticides; Pharmacodynamics; Phase; Phosgene; Pilocarpine; Pilot Projects; Population; Principal Investigator; Property; Radiation; Rattus; Receptor Signaling; Reduced Glutathione; Regimen; Research Project Grants; Safety; Sarin; Seizures; Soman; Subcutaneous Injections; Subway; Superoxides; Techniques; Testing; Therapeutic; Tokyo; Toxic effect; Treatment Efficacy; United States National Institutes of Health; War; Work; analytical tool; base; chemical threat; cholinergic; efficacy testing; fluoro jade; indexing; lung injury; mitochondrial dysfunction; nerve agent; neuron loss; neuroprotection; novel; perhydroxyl radical; prevent; programs; response; toxic organophosphate insecticide exposure; toxicant

DESCRIPTION (provided by applicant): Chemical warfare agents are a threat to both the civilian population and military personnel and there is an urgent need for rapid development of medical countermeasures. Controlling seizure activity and downstream consequences is critical for neuroprotection and survival after organophosphate (OP) exposure. The goal of this research project is to develop a novel and efficacious neuroprotective countermeasure against OP nerve agents. Recent efforts by the NIH CounterACT program to develop medical countermeasures have identified AEOL10150 as a lead compound that rescues lung injury caused by mustard and chlorine. The goal of this project is to determine if AEOL10150 is a neuroprotective medical countermeasure against a model OP and a primary nerve agent. Based on our preliminary results and prior work using a surrogate nerve agent, catalytic removal of reactive species by AEOL10150 is predicted to blunt oxidative stress and thereby prevent downstream changes such as neuronal loss and cognitive dysfunction. Specific goals of the project are to characterize oxidative stress as a target in two OP models, determine pharmacokinetics, bioavailability, and neuroprotective efficacy of AEOL10150 in these models using a variety of biochemical, pharmacological and analytical tools and techniques. These studies can help identify AEOL10150 as a versatile medical countermeasure against chemical warfare agents.

描述（由申请人提供）：化学战剂对平民和军事人员都构成威胁，迫切需要快速开发医疗对策。控制癫痫活动和下游后果对于有机磷 (OP) 暴露后的神经保护和生存至关重要。该研究项目的目标是开发一种针对 OP 神经毒剂的新型有效的神经保护对策。 NIH CounterACT 计划最近致力于开发医疗对策，已确定 AEOL10150 是一种先导化合物，可以挽救芥末和氯引起的肺损伤。该项目的目标是确定 AEOL10150 是否是针对模型 OP 和主要神经毒剂的神经保护性医疗对策。根据我们的初步结果和之前使用替代神经毒剂的工作，AEOL10150 催化去除活性物质预计可减弱氧化应激，从而防止神经元损失和认知功能障碍等下游变化。该项目的具体目标是表征氧化应激作为两个 OP 模型中的目标，使用各种生化、药理学和分析工具和技术确定 AEOL10150 在这些模型中的药代动力学、生物利用度和神经保护功效。这些研究有助于将 AEOL10150 确定为针对化学战剂的多功能医疗对策。